Objectives

Two-thirds of individuals living with Alzheimer's disease are women. Declining estrogen levels influence mood and cognition. Cumulative lifetime estrogen exposure (CLEE) correlates with cognition later in life. We examined the relationship of CLEE to depression and cognition in older women with major depression compared to non-depressed women.

Design

Older women (age ≥60 years) with depression were compared to non-depressed women using a lifetime estrogen exposure questionnaire. CLEE was defined as combined durations of reproductive span (age of menopause minus age of menarche) and any post-menopausal hormone replacement therapy use. Higher vs lower CLEE groups were based on a median of 474 months of estrogen exposure.

Setting

University hospital outpatient research program.

Participants

135 women ≥60 years; 64 depressed and 71 non-depressed.

Measurments

Participants completed a comprehensive cognitive test battery. General linear models were used to examine the association between cognitive domain scores and CLEE in depressed and non-depressed women, controlling for age, education, and ethnicity.

Results

Depressed and non-depressed groups had significantly different levels of CLEE, measured in months: mean 495.7 (SD 108.6) vs 456.4 (SD 66.0) months, F(1,130) = 5.01, p = .03. Within the non-depressed participants, higher CLEE was associated with improved delayed recall (F(1,59) = 5.94, p = .02, effect size = .61), while no such relationship was observed in the depressed group.

Conclusion

Higher CLEE was associated with improvement in delayed recall among non-depressed, but not among depressed participants. This suggests a protective role of estrogen on memory in non-depressed older postmenopausal women. Further research should examine the role of the CLEE in antidepressant response and cognitive decline.

Introduction

Geriatric depression is frequently accompanied by cognitive complaints and inflammation that increase risk for treatment-resistant depression and dementia. Memantine, a neuroprotective drug, can improve depression, inflammation, and help prevent cognitive decline. In our six-month clinical trial, escitalopram/memantine (ESC/MEM) improved mood and cognition compared to escitalopram/placebo treatment (ESC/PBO; NCT01902004). In this report, we examined the impact of baseline inflammation on mood and cognitive outcomes.

Materials and methods

We measured a panel of inflammatory cytokine markers using Human 38-plex magnetic cytokine/chemokine kits (EMD Millipore, HCYTMAG-60K-PX38) in 90 older adults 60 years and older with major depression enrolled in a 6-month double-blind placebo-controlled trial of escitalopram ​+ ​memantine (ESC/MEM) in depressed older adults with subjective memory complaints. Four cytokine factors were derived and linear models were estimated to examine the predictive ability of cytokine levels on treatment induced change in depression and cognition.

Results

Of the 90 randomized participants, 62 completed the 6-month follow up assessment. Both groups improved significantly on depression severity (HAM-D score), but not on cognitive outcomes at six months. Cytokine factor scores were not significantly different between ESC/MEM (n ​= ​45) and ESC/PBO (n ​= ​45) at baseline. Pro-inflammatory biomarkers at baseline predicted a decline in executive functioning in the ESC/PBO group but not in the ESC/MEM group, interaction F(1,52) ​= ​4.63, p ​= ​.04.

Discussion

In this exploratory analysis, the addition of memantine to escitalopram provided a protective effect on executive functioning in older depressed adults. Future studies are needed to replicate the association of cytokine markers to antidepressant and neuroprotective treatment-related change in cognition in geriatric depression.

Subjective cognitive decline (SCD) and mild cognitive impairment (MCI) accompanied by cerebrovascular risk factors (CVRFs) are known to increase the risk of developing dementia. Mind-body practices such as yoga and meditation, have been recognized as safe techniques with beneficial effects on cognitive functions in older adults at risk for cognitive decline. We conducted a randomized, controlled trial to assess the efficacy of Kundalini yoga training (KY) compared to memory enhancement training (MET) on mood and cognitive functioning in a group of older women with CVRFs and SCD (clinicaltrials.gov = NCT03503669). The KY intervention consisted of weekly, 60-min in-person classes with a certified instructor for 12 weeks, with a 12-min guided recording for daily homework practice at home. MET involved 12 weekly in-person group classes with 12-min daily homework exercises. Objective and subjective memory performance were the primary outcomes. Peripheral whole blood samples were collected at baseline, 12-weeks, and 24-weeks follow-up for RNA sequencing and cytokine/chemokine assays. A total of 79 patients (KY = 40; MET = 39) were randomized, and 63 completed the 24-week follow-up (KY = 65% completion rate; MET = 95%; χ2(1) = 10.9, p < 0.001). At 24-weeks follow-up, KY yielded a significant, large effect size improvement in subjective cognitive impairment measures compared to MET. KYOn a transcriptional level, at 12- and 24-week follow-up, KY uniquely altered aging-associated signatures, including interferon gamma and other psycho-neuro-immune pathways. Levels of chemokine eotaxin-1, an aging marker, increased over time in MET but not KY participants. These results suggest clinical and biological benefits to KY for SCD, linking changes in cognition to the anti-inflammatory effects of yoga.

Background

Geriatric depression with subjective cognitive complaints increases the risk of Alzheimer's Disease (AD). Memantine is a cognitive enhancer used to treat AD. In a 6-month double-blind randomized placebo-controlled trial of escitalopram and memantine (ESC/MEM), ESC/MEM improved cognition at 12 month in geriatric depression (NCT01902004). We now investigated structural neuroplastic changes at 3 months.

Methods

Forty-one older depressed adults (mean age=70.43, SD=7.33, 26 female) were randomized to receive ESC/MEM or ESC/PBO. Mood scores (Hamilton Depression Rating Scale, HAMD) and high-resolution structural T1-weighted images were acquired at baseline and 3 months. Freesurfer 6.0 for image processing and General Linear Models was used to examine group differences in symmetrized percent change gray matter volume (GMV) and cortical thickness, controlling for age and intracranial volume. Nonparametric tests were used to investigate group differences in mood and subcortical volume change.

Results

Among 27 completers (ESC/MEM n = 13; ESC/PBO n = 14), 62% achieved remission (HAMD≤6) with ESC/MEM and 43% with ESC/PBO (Fisher's exact p=.45). Change in HAMD did not differ between groups (F(1,23)=0.14, p=.7). GMV and thickness increased more with ESC/MEM than with ESC/PBO in the left middle and inferior temporal lobe, right medial, and lateral orbito-frontal cortex (OFC).

Limitations

included small sample size, dropout, and the lack of cognitive data at 3 months.

Conclusions

Although significant group differences in mood improvement were not observed, ESC/MEM resulted in increased GMV and cortical thickness in several brain regions compared to placebo. Larger longitudinal clinical trials can further examine the neuroprotective effect of memantine in geriatric depression.

Background

Increasing understanding of the neural correlates of anxiety symptoms in late-life depression (LLD) could inform the development of more targeted and effective treatments.

Methods

Grey matter volume (GMV) was assessed with volumetric magnetic resonance imaging in a sample of 113 adults ≥60 years with MDD using the following regions of interest: amygdala, anterior cingulate cortex (ACC), insula, orbitofrontal cortex (OFC), and temporal cortex.

Results

After controlling for demographic (age, sex, education) and clinical variables (antidepressant use, anxiolytic use, duration of illness, medical comorbidity, cognitive functioning), greater severity of anxiety symptoms was associated with lower GMV bilaterally in the insula, F(1,102) = 6.63, p = 0.01, and OFC, F(1,102) = 8.35, p = 0.005. By contrast, depressive symptom severity was significantly associated with lower bilateral insula volumes, F(1,102) = 6.43, p = 0.01, but not OFC volumes, F(1,102) = 5.37, p = 0.02.

Limitations

Limitations include (1) the relatively mild nature of anxiety symptoms in our sample; (2) the cross-sectional research design, which prohibits inferences of directionality; (3) the relatively homogenous demographic of the sample, and (4) the exclusion of participants with significant psychiatric comorbidity, suicidality, or cognitive impairment.

Conclusions

Decreased OFC volumes may serve as a unique biomarker of anxiety symptoms in LLD. Future longitudinal and clinical studies with long-term follow up and more diverse samples will help further elucidate the biological, psychological, and social factors affecting associations between anxiety and brain morphology in LLD.

Background and objectives

Women who breastfeed may experience long-term benefits for their health in addition to the more widely appreciated effects on the breastfed child. Breastfeeding may induce long-term effects on biopsychosocial systems implicated in brain health. Also, due to diminished breastfeeding in the postindustrial era, it is important to understand the lifespan implications of breastfeeding for surmising maternal phenotypes in our species' collective past. Here, we assess how women's breastfeeding history relates to postmenopausal cognitive performance.

Methodology

A convenience sample of Southern California women age 50+ was recruited via two clinical trials, completed a comprehensive neuropsychological test battery and answered a questionnaire about reproductive life history. General linear models examined whether cognitive domain scores were associated with breastfeeding in depressed and non-depressed women, controlling for age, education and ethnicity.

Results

Women who breastfed exhibited superior performance in the domains of Learning, Delayed Recall, Executive Functioning and Processing Speed compared to women who did not breastfeed (P-values 0.0003-0.015). These four domains remained significant in analyses limited to non-depressed and parous subsets of the cohort. Among those depressed, only Executive Functioning and Processing Speed were positively associated with breastfeeding.

Conclusions and implications

We add to the growing list of lifespan health correlates of breastfeeding for women's health, such as the lower risk of type-2 diabetes, cardiovascular disease and breast cancer. We surmise that women's postmenopausal cognitive competence may have been greater in past environments in which breastfeeding was more prevalent, bolstering the possibility that postmenopausal longevity may have been adaptive across human evolutionary history.

Lay summary

Breastfeeding may affect women's cognitive performance. Breastfeeding's biological effects and psychosocial effects, such as improved stress regulation, could exert long-term benefits for the mother's brain. We found that women who breastfed performed better on a series of cognitive tests in later life compared to women who did not breastfeed.

Objectives

Geriatric depression is difficult to treat and frequently accompanied by treatment resistance, suicidal ideations and polypharmacy. New adjunctive mind-body treatment strategies can improve clinical outcomes in geriatric depression and reduce risk for side-effects of pharmacological treatments.

Methods

We conducted a 3-month randomized controlled trial to assess the efficacy and tolerability of combining Tai Chi Chih (TCC) or Health Education and Wellness training (HEW) with the stable standard antidepressant treatment on mood and cognitive functioning in depressed older adults (NCT02460666). Primary outcome was change in depression as assessed by the Hamilton Rating Scale for Depression (HAM-D) post-treatment. Remission was defined as HAM-D ≤ 6; naturalistic follow-up continued for 6 months. We also assessed psychological resilience, health-related quality of life and cognition.

Results

Of the 178 randomized participants, 125 completed the 3-month assessment and 117 completed the 6-month assessment. Dropout and tolerability did not differ between groups. Remission rate within TCC was 35.5% and 33.3%, compared to 27.0% and 45.8% in HEW, at 3 and 6 months respectively (χ²(1) = 1.0, p = 0.3; χ²(1) = 1.9, p =0.2). Both groups improved significantly on the HAM-D at 3 and 6 months. TCC demonstrated a greater improvement in general health compared to HEW.

Conclusions

Both TCC and HEW combined with a standard antidepressant treatment improved symptoms of depression in older adults. While TCC was superior to HEW in improving general health, we did not find group differences in improvement in mood and cognition.

Background: Geriatric depression with subjective memory complaints increases the risk for Alzheimer's Disease. Memantine, a neuroprotective drug, can improve depression and help prevent cognitive decline. In our 6-months clinical trial, escitalopram/memantine (ESC/MEM) improved mood and cognition compared to escitalopram/placebo treatment (ESC/PBO; NCT01902004). In this report, we investigated whether baseline brain white matter integrity in fronto-limbic-striatal tracts can predict clinical outcomes using fractional anisotropy (FA). Methods: Thirty-eight older depressed adults (mean age = 70.6, SD = 7.2) were randomized to ESC/MEM or ESC/PBO and underwent diffusion-weighted imaging (DWI) at 3 Tesla at baseline. Mood was assessed using the Hamilton Depression Rating Scale (HAMD), apathy using the Apathy Evaluation Scale (AES) and anxiety using the Hamilton Anxiety Scale (HAMA) at baseline and 6-months follow-up. FA was extracted from seven tracts of interest (six in each hemisphere and one commissural tract) associated with geriatric depression. Non-parametric General Linear Models were used to examine group differences in the association between FA and symptom improvement, controlling for age, sex, baseline symptom scores and scanner model, correcting for false discovery rate (FDR). Post-hoc tests further investigated group differences in axial, mean and radial diffusivity (AD, MD, and RD, respectively). Lastly, we performed an exploratory whole-brain model to test whether FA might be related to treatment response with memantine. Results: There were no differences in remission rates or HAMD change between groups. In bilateral anterior and posterior internal capsule tracts and bilateral inferior and right superior fronto-occipital (IFO and SFO) fasciculus, higher FA was associated with larger improvements in depressive symptoms for ESC/MEM, but not ESC/PBO, correcting for FDR. Lower MD in the left IFO and RD in the right anterior internal capsule were associated with improved treatment responses. We found no significant associations in the whole-brain analysis. Limitations: Included small sample size and high dropout. Conclusions: Higher baseline FA and lower RD and MD in hypothesized fronto-limbic-striatal tracts predicted greater improvement in mood and anxiety with ESC/MEM compared to ESC/PBO in geriatric depression. FA as a biomarker for white matter integrity may serve as a predictor of treatment response but requires confirmation in larger future studies.

Background

As an adjunct to antidepressant treatment, Tai Chi Chih (TCC) is superior to health education and wellness (HEW) training in improving the general health of patients with geriatric depression (GD). This study investigated the brain connectivity changes associated with TCC and HEW in combination with antidepressant treatment in patients with GD.

Methods

Forty patients with GD under stable antidepressant treatment underwent TCC training (n = 21) or HEW training (n = 19) for 12 weeks, and completed baseline and 3-month follow-up resting state magnetic resonance imaging scans. Within-group and between-group differences in parcel-to-parcel connectivity changes with intervention were evaluated by general linear modeling. Relationships between significant connectivity changes and symptom/resilience improvement were evaluated by partial least squares correlation analysis.

Results

Significantly greater increases in connectivity with TCC than with HEW (FDR-corrected p < .05) were observed for 167 pairwise connections, most frequently involving the default mode network (DMN). In both groups, increased connectivity involving largely DMN regions was significantly and positively correlated with improvement in symptoms/resilience.

Limitations

The sample size was relatively small, mainly due to neuroimaging contraindications (e.g., implants). Additionally, the standard antidepressant treatment varied greatly among patients, adding heterogeneity.

Conclusions

Non-pharmacological adjuncts, such as TCC, may enhance DMN connectivity changes associated with improved depressive symptoms and psychological resilience in the treatment of GD.

Growing evidence supports the concept that bidirectional brain-gut microbiome interactions play an important mechanistic role in aging, as well as in various neuropsychiatric conditions including depression. Gray matter volume (GMV) deficits in limbic regions are widely observed in geriatric depression (GD). We therefore aimed to explore correlations between gut microbial measures and GMV within these regions in GD. Sixteen older adults (>60 years) with GD (37.5% female; mean age, 70.6 (SD = 5.7) years) were included in the study and underwent high-resolution T1-weighted structural MRI scanning and stool sample collection. GMV was extracted from bilateral regions of interest (ROI: hippocampus, amygdala, nucleus accumbens) and a control region (pericalcarine). Fecal microbiota composition and diversity were assessed by 16S ribosomal RNA gene sequencing. There were significant positive associations between alpha diversity measures and GMV in both hippocampus and nucleus accumbens. Additionally, significant positive associations were present between hippocampal GMV and the abundance of genera Family_XIII_AD3011_group, unclassified Ruminococcaceae, and Oscillibacter, as well as between amygdala GMV and the genera Lachnospiraceae_NK4A136_group and Oscillibacter. Gut microbiome may reflect brain health in geriatric depression. Future studies with larger samples and the experimental manipulation of gut microbiome may clarify the relationship between microbiome measures and neuroplasticity.